The farnesoid X receptor (FXR), the peroxisome proliferator-activated receptor α (PPARα), and the liver X receptor α (LXRα) are members of a superfamily of approximately 150 proteins that bind to cis-acting elements in the promoters of their target genes and modulate gene expression in response to hormone activators or ligands. For many of these receptors, the activators are known, while for others, termed “orphan receptors,” the activators are unknown. Furthermore, some of these receptors bind to their target genes as dimers consisting of two molecules of the same receptor (homodimers), while others bind as dimers consisting of one molecule each of two different receptors (heterodimers). Prominent among the latter are nuclear receptors that require heterodimerization with the retinoid X receptor (RXR), as disclosed in Yu et al. Cell 67:1251-1266 (1991). Members of this group include the vitamin D receptor, the thyroid hormone receptor (T3R), the retinoic acid receptor (RAR), FXR, the peroxisome proliferator-activated receptors (PPARs) and LXR α.
FXR was first reported by Forman and coworkers, Forman Cell 81:687-693 (1995). This receptor is a protein having a relative molecular mass (Mr) of approximately 54,000, and is a vertebrate transcription factor regulated by intracellular metabolites. The receptor is activated by certain farnesoids, i.e., farnesol, compounds derived from farnesol, and/or compounds similar in structure to farnesol. These farnesoids include farnesol, farnesal, farnesyl acetate, farnesoic acid, geranylgeraniol and juvenile hormone III.
FXR is a nuclear receptor thought to be involved in negatively controlling the expression level of cholesterol 7α-hydroxylase (cyp7a), the rate-limiting enzyme involved in the oxidative metabolism of cholesterol into bile acids. As such, modulators of FXR activity will find utility in diseases associated with abnormally high or low cholesterol levels. Of particular value will be FXR antagonists, which block the negative feedback downregulation of cyp7a expression produced by certain cholic acids, the endogenous ligands for FXR. FXR is also involved in controlling the synthesis of isoprenoid derivatives (including cholesterol), and the proliferation of certain types of cancerous cells, such as those derived from colon carcinomas. Additionally, since FXR forms heterodimers with RXR in some cell types, modulation of the level of FXR activity in a cell has a wide range of effects on a variety of biological processes which are mediated by RXR or other RXR-interacting proteins such as PPARγ and PPARα. These other biological activities include, among others, obesity, diabetes, lipid associated disorders, cancer, inflammatory disorders, disorders involving a disrupted or dysfunctional epidermal barrier, and various other metabolic disorders. Modulators of FXR, both agonists and antagonists, will find utility in treating one or more of these diseases.
PCT Publication No. WO 00/40965, which is incorporated herein by reference, describes methods and compositions that are useful for modulating cholesterol levels in a cell and methods for identifying compounds that can be tested for ability to modulate cholesterol levels in mammals. These methods involve analyzing the effect of a test compound on the binding of FXR to an FXR ligand. Such ligands include, for example, bile acids, coactivators, and corepressors. The methods and compositions involve modulating FXR-mediated expression of genes involved in cholesterol metabolism.
Despite the advances made by WO 00/40965, there is a need in the art for new FXR modulators, both antagonists and agonists, to be used for a variety of indications. The present invention remedies this and other needs.